The neurohypophysial hormones arginine8-vasopressin (AVP) and oxytocin (OT) exert pivitol roles in maintaining body homeostasis and are especially important as neuroendocrine modulators of physiological and behavioural stress responses. We are investigating the nature (structure), distribution and physiological role of the receptors for these hormones. We have previously cloned the cDNAs for the "known" rodent and human AVP receptor subtypes (V1a, V1b, and V2), and the OT receptor. The rat AVP V1b (pituitary) receptor gene has now been isolated which will allow studies exploring its tissue-specific expression and regulation in the pituitary, brain and peripheral tissues. The mouse V1b (and OT) receptor gene has been isolated and will be used to create targeting constructs to produce null mutant ("knockout") mice in which the function(s) of the receptor is disrupted. Additional studies are focused on determining the cellular expression of the V1b- and V2- receptor genes in rat and human tissues by in situ hybridization histochemistry. We have shown that vasopressin metabolites (VP4-8/VP4-9) stimulate intracellular Ca2+ mobilization in a subpopulation of cultured rat pineal cells. This observation provides a basis upon which an attempt is being made to clone the vasopressin metabolite binding site (receptor) by functional expression of a pineal cDNA library in Xenopus oocytes. The vasopressin metabolite receptor (or a closely related subtype) may be involved in the reported effects of AVP (and its metabolites) on memory in rats, and in humans with post-traumatic amnesia, Alzheimer's disease, aging and schizophrenia.